ALL blood-wetted devices, without exaggeration, are susceptible to unintended thrombosis and bleeding ? with dire consequences. In spite of decades of clinical experience, basic research, and computational fluid dynamics modeling, it is still virtually impossible to avoid deleterious hematological effects without experimental trail-and-error. In fact, in recent years, the incidence of thromboembolic and hemorrhagic adverse events in ventricular assist devices (VADs) has increased, not decreased. The unfortunate consequence is an unacceptable rate of debilitating adverse events such as stroke and hemorrhage. This has motivated the PI and colleagues over the past two decades to develop an accurate, computational model to simulate the process of thrombus deposition on artificial surfaces. The computer simulation is unique in its ability to account for physical and biological phenomena on multiple-scales, including the trafficking of red blood cells and platelets in small spaces, synthesis and transport of chemical agonists, and several pathways for positive- and negative feedback of platelet adhesion to artificial surfaces. The current model has demonstrated excellent agreement with experimental observations in microfluidic channels and the HeartMate-2 blood pump. The objective of this competitive renewal is to continue improvement of the versatility of this model, and to demonstrate its translation to full-scale blood-wetted devices. The two Specific Aims of this study are: SA1, to improve the fidelity of the model by adding important mechanisms of platelet disaggregation, thrombolysis, and von Willebrand mediated platelet adhesion; and SA2, to demonstrate and further validate the performance of the model with contemporary blood pumps and oxygenators in clinical use. Successful completion of these aims will yield a comprehensive computational model for thrombosis in blood-wetted devices, which we believe will contribute to the inevitable paradigm shift in developing these devices: replacing trial-and-error with prescriptive quantitative methods. Combined with computer optimization, the use of this model will greatly accelerate development of safe and effective new devices, and will reduce the occurrence of adverse complications. We also envision that the models will also be used forensically to analyze thrombosis-related adverse events, and help guide management of anticoagulation therapy.